Abstract
Fusing antigens to chemokines to target antigen presenting cells (APC) is a promising method for enhancing immunogenicity of DNA vaccines. However, it is unclear how different chemokines compare in terms of immune potentiating effects. Here we compare Ccl3- and Xcl1-fusion vaccines containing hemagglutinin (HA) from influenza A delivered by intramuscular (i.m.) or intradermal (i.d.) DNA vaccination. Xcl1 fusion vaccines target cDC1s, and enhance proliferation of CD4+ and CD8+ T cells in vitro. In contrast, Ccl3 target both cDC1 and cDC2, but only enhance CD4+ T cell proliferation in combination with cDC2. When Ccl3- or Xcl1-HA fusion vaccines were administered by i.m. DNA immunization, both vaccines induced Th1-polarized immune responses with antibodies of the IgG2a/IgG2b subclass and IFNγ-secreting T cells. After i.d. DNA vaccination, however, only Xcl1-HA maintained a Th1 polarized response and induced even higher numbers of IFNγ-secreting T cells. Consequently, Xcl1-HA induced superior protection against influenza infection compared to Ccl3-HA after i.d. immunization. Interestingly, i.m. immunization with Ccl3-HA induced the strongest overall in vivo cytotoxicity, despite not inducing OT-I proliferation in vitro. In summary, our results highlight important differences between Ccl3- and Xcl1- targeted DNA vaccines suggesting that chemokine fusion vaccines can be tailor-made for different diseases.
Highlights
Fusing antigens to chemokines to target antigen presenting cells (APC) is a promising method for enhancing immunogenicity of DNA vaccines
Consistent with this interpretation, Xcl1mCherry selectively induced chemotaxis of conventional dendritic cell type 1 (cDC1) in a transwell chemotaxis assay, while Ccl3-mCherry induced a similar degree of chemotaxis of both cDC1 and cDC2 (Fig. 1B)
To investigate if Xcl[1] or Ccl[3] could directly activate cDCs, BM dendritic cell (DC) were incubated with 0.5 μg anti-NIP, Ccl3- or Xcl1-mCherry for 18 h and the expression of CD40, CD80 and CD86 evaluated by flow cytometry
Summary
Fusing antigens to chemokines to target antigen presenting cells (APC) is a promising method for enhancing immunogenicity of DNA vaccines. It is unclear how different chemokines compare in terms of immune potentiating effects. When Ccl3- or Xcl1-HA fusion vaccines were administered by i.m. DNA immunization, both vaccines induced Th1-polarized immune responses with antibodies of the IgG2a/IgG2b subclass and IFNγ-secreting T cells. Different strategies have been developed in order to improve the immunogenicity of DNA vaccines, including electroporation (EP) of the injection site in order to enhance antigen expression[1], or fusing antigens to chemokines or single-chain variable fragments (scFV) in order to target antigen presenting cells (APC)[2,3]. DNA vaccination, with or without EP, is more efficient at inducing cellular immune responses in both mice and macaques[23,24]
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